AKT1 (v-akt murine thymoma viral oncogene homolog 1) dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Decreased AKT1 protein levels have been observed in lymphoblasts and postmortem prefrontal cortices of patients with schizophrenia furthering the plausibility that these findings relate to the pathophysiology of psychosis. This observation led to initial evidence of genetic association of AKT1 with schizophrenia, a finding that has been reported in at least 4 studies. Some studies, however, have not found association between AKT1 and schizophrenia, and there have been inconsistencies across studies in SNPs (single nucleotide polymorphisms) and alleles showing the strongest association. Thus, the AKT1 association with schizophrenia has been tentative, although even if the genetic association were valid, inconsistency might not be surprising given the impact of phenotypic and genetic heterogeneity and the importance of gene-gene and gene-environment interactions. We studied AKT1 effects on human subjects at several phenotypic levels in 319 individuals in terms of cognitive tests, a subset of 32 individuals in terms of AKT1 protein expression in lymphoblasts, independent subsets of 46 and 68 individuals in terms of fMRI (functional magnetic resonance imaging) of brain, and an overlapping set of 171 individuals for structural brain MRI. In this study we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts, influences several brain measures related to dopamine function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with AKT1 variation. The functional impact of AKT1 genetic variation on gene expression was based on the positive association of an AKT1 mutation (rs1130233) with cognition in our normal sample. We determined the effect of this altered AKT1 protein in peripheral lymphoblasts derived from a subset of the healthy subjects used in our cognitive and imaging association analyses. This same SNP is functional or monitors another functional variant is suggested by an earlier study showing an association of its minor A allele with reduced AKT1 protein levels and increased apoptosis (programmed cell death) following irradiation stress in human lymphoblasts. We confirmed that individuals who are carriers of the A allele had significantly reduced AKT1 protein levels compared with major allele individuals. Our strategy has taken a genetic association of AKT1 with brain phenotypes related to dopamine function to examine in humans, a potential effect of AKT1 on dopamine-mediated cellular function implicated in basic studies. One of our past studies suggested a potential molecular pathway involved in the neurodevelopmental origins of schizophrenia. In that study, we examined cell adhesion, as an essential component of cell motility. In our assay, NRG1 (neuregulin-1) induced lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. NRG1 adhesion variation is blocked by ErbB2 (erythroblastic leukemia viral oncogene homolog 2), PI3K (phosphotidylinositol 3 kinase), and AKT inhibitors, but not by PLC (phospholipase C precursor), ROCK (Rho-associated, coiled-coil containing protein kinase), MLCK (myosin light chain kinase) or MEK (mitogen-activated protein or extracellular signal-regulated kinases) inhibitors, implicating the ErbB2/PI3K/AKT1 signaling pathway in NRG1-stimulated cell adhesion. In cell lines from 20 schizophrenia patients and 20 healthy controls, cells from the schizophrenia patients showed significant deficiency in the range of NRG1 induced adhesion. The COMT (catechol-o-methyltransferases) valine158methionine genotype demonstrated a strong trend towards predicting the range of the NRG1 induced adhesion response with risk alleles, Valine/valine having decreased variation in cell adhesion even in healthy controls. Our findings suggested that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.